Although the rate of cancer incidence has declined since 1990, the number of people in the U.S. who are expected to die in 2004 from cancer is still expected to exceed half a million. The five most prevalent types of cancer in the U.S., ranked by the estimated number of new cases for the year 2004 (excluding base and squamous cell cancers of the skin), are as follows: prostate, female breast, lung and bronchus, colon and rectum, and urinary bladder. Breast cancer is the leading cause of cancer in U.S. women, with approximately 216,000 new cases diagnosed and 40,000 deaths per year.
Several modalities, including radiation, chemotherapy, and surgery, either alone or in combination, are being used for the treatment of cancer. Because of these treatments, most patients with skin cancer, and about half the people treated for internal cancers, are completely freed of their disease. However, the therapies now available for internal cancers often give rise to side effects so harmful that they compromise the benefits of treatment, and existing therapies for such internal cancers often fail in many cases. Radiation and surgery are limited in that they cannot treat widespread metastases that eventually form full fledged tumors at numerous sites. In the 1960's it was discovered that chemotherapy could cure some cancers when several drugs were given in combination. Unfortunately, the most common cancers (breast, lung, colorectal, and prostate cancer) are not yet curable with chemotherapy alone.
Enzyme prodrug therapy was proposed in the mid-1980's as a means of restricting the action of cytotoxic drugs to tumor sites, thereby increasing their efficacy and reducing their normal tissue toxicity. Enzyme prodrug therapy is a two-step approach. In the first step, a drug-activating enzyme is targeted to the tumor cells. In the second step, a nontoxic prodrug, a substrate of the exogenous enzyme that is not expressed in tumors, is administered systemically. The net gain is that a systemically administered prodrug can be converted to high local concentration of an active anticancer drug in tumors. The enzyme should be either of nonhuman origin or a human protein that is absent or expressed only at low concentrations in normal tissues. The enzyme prodrug systems developed to date have used antibodies to target the enzyme to the tumor, and this therapy has been called antibody-directed enzyme prodrug therapy (ADEPT). Drawbacks of ADEPT include poor accessibility of the enzyme/antibody conjugate to the tumor, the cost and difficulties with development and purification of antibodies, and immunogenicity of both the antibody and the enzyme (G. Xu and H. L. McLeod, 2001, Strategies for enzyme/prodrug cancer therapy, Clinical Cancer Research, 7:3314-3324).
Results obtained over the past 40 years have demonstrated that tumor cells of all types tested have an elevated growth requirement for methionine compared to normal cells (Miki et al., 2000). Numerous lines of cancer cells are unable to survive and grow when the amino acid methionine is replaced in the medium with homocystine. However, normal adult cell lines survive and grow well with this substitution. For example, Halpern et al. (1974) showed that breast carcinosarcoma and lymphatic leukemia cells did not retain viability after 20 days in media devoid of methionine but with added homocystine. On the other hand, normal liver fibroblasts, breast fibroblasts, and prostate fibroblasts grew normally under these same conditions. Further studies have shown that methionine-dependent cells arrest in the G2 and G1 phases of the cell cycle and subsequently die at methionine concentrations less than 5 μM regardless of high concentrations of homocystine precursors and folates (Kokkinakis et al., 1997a).
Subsequent to the tests of the effect of methionine on cancer and normal cells in cell culture, there have been in vivo tests of the effect of methionine depletion on cancer cells. One comprehensive study was performed on mice with human brain tumor xenografts (Kokkinakis et al., 1997b). With a combination of dietary restriction of methionine, homocysteine, and choline and synchronous treatments with intraperitoneal injections of L-methioninase (44 mg/kg per day of L-methioninase) and homocystine, tumor stasis was achieved in 100% of treated animals within four days of treatment, and regression was seen in one-third of animals after a 10-day period. The methioninase produced no toxicity in the mice.
However, the current methioninase experimental methodologies require large dosages of methioninase as well as methionine-, homocystine-, and choline-restricted diets.
Therefore, there is a need in the art for new and improved methods of targeting anticancer agents specifically to the surface of cancer cells, or specifically to the surface of blood vessels supplying the cancer cells. It is to such methods of targeting anticancer agents to the surface of cancer cells or blood vessels supplying the cancer cells, thereby requiring significantly lower dosages of anticancer agents than current methods, and thus overcoming the disadvantages and defects of the prior art, that the presently disclosed and claimed inventive concept(s) is directed.